The Molecular Identification Of FoxP3 +ve Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$483,273.00
Summary
The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and rheumatoid arthritis. One of the key players in the maintenance of a h ....The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and rheumatoid arthritis. One of the key players in the maintenance of a healthy immune system is a specialized set of T cells known as T Regulatory cells. These cells are rare, at 1-4% of all T cells, yet are potent modulators of other T cells, and can prevent the activation of a T cell if it is reacting to a self-antigen. If they can control the cause of autoimmune disease, and patient Treg cells can be manipulated, it may be possible to use them therapeutically. Recently the switch that is required to generate regulatory cells was identified from patients with a rare autoimmune disease called Immunodysregulation, polyendocrynopathy, enteropathy, X-linked syndrome or IPEX. A mouse disease, Scurfy, with similar symptoms, is caused by the same mutations. The mutated gene encodes a protein, FoxP3, and this protein is able to bind to other genes in T cells and regulate their function. Without this protein, there are no T regulatory cells, resulting in autoimmune disorders. At this time there is very little known about how the FoxP3 gene is able to make a T cell become a regulatory T cell, and nothing is known about the genes that are turned off and on to facilitate this. If we can understand better the role of this protein, FoxP3, in the generation and maintenance of T cells with regulatory function, we may better be able to diagnose and treat autoimmune diseases, and this knowledge will have broad application to many autoimmune disorders.Read moreRead less
Microwave And Laser Energies For Percutaneous Cardiac Ablation For The Cure Of Arhythmias
Funder
National Health and Medical Research Council
Funding Amount
$331,527.00
Summary
The commonest beating disorder of the heart is atrial fibrillation (AF). Whilst it can occur at any age it is more common in the elderly with 12% Australians over 70 y.o having it. AF is the cause of a third of all strokes and increases the risk of dying from any heart disease. Ventricular tachycardia (VT) is the commonest cause of death in the year after a heart attack. Currently these beating disorders are in most cases incurable and respond poorly to medications. We have developed an operatio ....The commonest beating disorder of the heart is atrial fibrillation (AF). Whilst it can occur at any age it is more common in the elderly with 12% Australians over 70 y.o having it. AF is the cause of a third of all strokes and increases the risk of dying from any heart disease. Ventricular tachycardia (VT) is the commonest cause of death in the year after a heart attack. Currently these beating disorders are in most cases incurable and respond poorly to medications. We have developed an operation for AF which is done by open heart surgery. It has been successful at curing some patients who suffer from AF and uses radiofrequency energy. The difficulty of radiofrequency energy is that it is not suitable in a large number of cases for this operation. We are developing Laser and Microwave catheters as alternatives to RF so that the success of the operation can be improved. These new microwave and laser catheters are being designed and tested to be used primarily in a minimally invasive procedure. They would be inserted via the veins with the patient under sedation. This would allow patients to go home sooner and have a recovery period of only a few days. As well as their application in the top chamber of the heart (atrium) for AF, these new energies will be adapted for minimally invasive operations in the ventricle (lower chamber) of the heart for the treatment of ventricular tachycardia. By developing a technique such as this, cure of AFand VT will be available to many more people, helping reduce the strokes, heart failure and premature deaths from these two heart conditions.Read moreRead less
Treatment Of Genetic Liver Disease By Homologous Recombination In Vivo, Coupled With A Pharmoco-genetic Strategy For Selective Expansion Of Genetically Repaired Hepatocytes
Funder
National Health and Medical Research Council
Funding Amount
$920,836.00
Summary
This project seeks to exploit recent advancements in our ability to precisely “edit” and correct mutations underlying human genetic diseases. To improve therapeutic efficiencies of the system, we will deliver the technology using highly efficient virus-based systems and apply a novel post-repair selection process to preferentially repopulate the liver with gene-repaired cells. Demonstration of the strategy in a humanised mouse model will provide important preclinical data for human applications.
Targeting CD4-positive Cells For Anti-HIV Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$356,646.00
Summary
Treatment of HIV early following infection is thought to be important for maximising the quality of life of patients. Conventional therapy has had some success in early intervention but resistance invariably develops. This application proposes to develop a gene therapy approach to elimiate HIV infected cells by introducing a suicide gene into those cells that harbor the virus. The advantage of this approach is the limited toxicity that is associated with gene therapies as well as the ability to ....Treatment of HIV early following infection is thought to be important for maximising the quality of life of patients. Conventional therapy has had some success in early intervention but resistance invariably develops. This application proposes to develop a gene therapy approach to elimiate HIV infected cells by introducing a suicide gene into those cells that harbor the virus. The advantage of this approach is the limited toxicity that is associated with gene therapies as well as the ability to target specific cell-types. It is proposed to genetically modify a strain of adenovirus to introduce a gene that will kill cells that it infects that also contain HIV. This is a novel approach and potentially may be an important treatment in the future. Anti-HIV gene therapy may also be useful in addition to the more conventional treatments.Read moreRead less
Site-specific Integration Of Functional Genomic Loci: Applications In Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$442,664.00
Summary
Gene therapy strategies have traditionally focused on the delivery of therapeutic genes by viral vectors. Mindful of the limitations and potential problems of viral gene delivery, non-specific viral integration and limited transgene expression, this investigation will explore the delivery and site-specific integration of large genomic fragments into human stem cells. It is anticipated this approach will avoid some of the problems associated with poor gene expression and insertional oncogenesis.
Reconstitution Of B-cell Ontogeny In Btk-deficient Patient-derived CD34+ Cells In A Humanised Mouse Model: The Foundations For An Australian XLA Gene Therapy Trial
Funder
National Health and Medical Research Council
Funding Amount
$678,652.00
Summary
Gene therapy targeting the bone marrow has broad therapeutic potential in the management of genetic diseases, viral infections and cancers involving blood cells. In this proposal we plan to obtain bone marrow cells from patients with X-linked agammaglobulinaemia and show that their cells can be genetically repaired in the test tube and, when transferred back into a specialised mouse models, reconstitute the immune system. The results have the potential to underpin a human clinical trial.
Minimally-invasive Gene Delivery Of A Novel Inhibitor Of Retinal Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$883,883.00
Summary
Excessive growth of blood vessels in the eye causes vision loss and can only be treated with lasers or painful and frequent injections into the eye. Vasostatin is a specific inhibitor of angiogenesis and a promising agent for the management of ocular neovascularisation. We will provide pre-clinical evidence that gene delivery of vasostatin-like peptides is an effective therapeutic strategy and it has potential to revolutionize the current ophthalmic care of age-related macular degeneration.